Aromatic organozinc reagents as nucleophiles in the α-arylation of piperidine and tetrahydropyran

Article abstract of DOI:10.1016/j.tetlet.2005.11.070

The arylation at the α-position of piperidine derivatives is achieved in good yield using aromatic organozinc reagents and either 2-methoxylated or α-cyanated piperidine. Oxygen-containing heterocycles such as 2-methoxy-tetrahydropyran reacts in a same manner to yield efficiently 2-arylated tetrahydropyran.

Full text of DOI:10.1016/j.tetlet.2005.11.070

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 455–458
Aromatic organozinc reagents as nucleophiles in the a-arylation
of piperidine and tetrahydropyran
Erwan Le Gall,* Corinne Gosmini and Michel Troupel
`
Laboratoire d’Electrochimie, Catalyse et Synthese Organique, LECSO, CNRS-Universite Paris 12 Val de Marne,
´
UMR 7582, 2-8 rue Henri Dunant, 94320 Thiais, France
Received 20 October 2005; revised 10 November 2005; accepted 15 November 2005
Available online 1 December 2005
Abstract—The arylation at the a-position of piperidine derivatives is achieved in good yield using aromatic organozinc reagents and
either 2-methoxylated or a-cyanated piperidine. Oxygen-containing heterocycles such as 2-methoxy-tetrahydropyran reacts in a
same manner to yield efficiently 2-arylated tetrahydropyran.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Piperidine derivatives constitute an important class of
biologically-active compounds and numerous works
were devoted to their synthesis during the last decades.1
With respect to the predominance of 2-alkylated struc-
tures in natural products, procedures for alkylation of
the 2-position have been extensively studied.2 Fewer
works have been devoted to the 2-arylation and even less
to the arylation at the side chain of piperidine deriva-
tives. Nevertheless, it was shown that phenylmagnesium
chloride3 or pyridyllithium4 reacts with 2-activated pip-
eridines to provide the 2-aryl-piperidine derivatives in
good yields. Electron-rich substituted benzenes also
react with 2-methoxylated piperidines in the presence
of Lewis acids but the regioselectivity is governed by
the position of the most reactive aromatic carbon.5 By
another way, palladium catalysis allows the efficient
coupling of enamides6 or a-lithio amines7 with some aryl
iodides. Examples of rearrangements8 or cyclizations9
leading to 2-aryl piperidines have also been described.
Reductive aminations of aromatic aldehydes or ketones
corresponding to arylation at the a-position of the nitro-
gen substituent can be realized in the presence of
polymethylhydrosiloxane.10
ally considered as masked iminium equivalents, has not
been previously reported. However, a large variety of
functionalized aromatic organozinc derivatives are
accessible and due to their broad chemical tolerance
they constitute an interesting source of nucleophiles.11
In addition, it has been shown that aliphatic organozinc
compounds could act as nucleophile in Bruylants reac-
tions.12 Then, in a part of our work devoted to the study
of the reactivity of organozinc reagents, we investigated
their reactions with a-activated heterocyclic compounds
and we report herein our preliminary results.
We first synthesized several electrophilic a-substituted
heterocycles, which could act as valuable models
(Scheme 1). Methoxylated and cyanated piperidine
derivatives 1 to 3 were chosen as nitrogen-containing
heterocycles. In addition and in order to test the scope
of the reaction, we also synthesized an oxygenated het-
erocyclic compound, 2-methoxy-tetrahydropyran (4).
Thus, 2-phenyl-2-(piperidin-1-yl)acetonitrile (1) was eas-
ily synthesized starting from benzaldehyde and piper-
idine using a procedure described for the synthesis of
(N,N-dimethylamino)phenylacetonitrile.13 For the syn-
thesis of 1-phenylpiperidine-2-carbonitrile (2), the first
step was the phenylation of the nitrogen atom of piper-
idine.14 The subsequent cyanation of 1-phenylpiperidine
to form compound 2 was achieved electrochemically in
70% yield.15 Other iminium equivalents, such as a-ami-
noethers, being widely used elsewhere in alkylation reac-
tions, we synthesized 3 in two steps starting from
piperidine, which was first converted into its N-Boc
derivative using di-tert-butyl dicarbonate according to
To the best of our knowledge, use of aromatic organo-
zinc reagents in the nucleophilic displacement of a-
methoxylated or cyanated piperidines, which are gener-
Keywords: Arylation; a-Aminoether; a-Aminonitrile; Acetal; Organo-
zinc reagent.
*
Corresponding author. Tel.: +(33) 1 49 78 11 36; fax: +(33) 1 49 78
11 48; e-mail: legall@glvt-cnrs.fr
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.070

456
E. Le Gall et al. / Tetrahedron Letters 47 (2006) 455–458
1. NaNH2
tBuOH
1. NaHSO3
- e-, NaCN
70%
PhCHO
2. piperidine,
NaCN
2. PhBr
N
N
H
N
N
CN
80%
65%
Ph
Ph
2
Ph
N
CN
1
MeOH, H+
95%
- e-, MeOH
79%
(BOC)2O
99%
O
O
OMe
N
H
N
OMe
4
BOC
BOC
3
Scheme 1.
a known method.16 tert-Butyl piperidine-1-carboxylate
so obtained was then converted to the N-protected a-
the reaction does not proceed fast enough and dimeriza-
tion of the organozinc reagent is observed.
aminoether
3
in 79% yield by electrochemical
methoxylation.17
It can be noted that contrary to what we have experi-
mented with methoxylated compounds, the use of an
additional strong Lewis acid is not necessary when the
electrophile is a cyanated compound (entries 1–4).
Cobalt salts remaining from the organozinc synthesis step
are still present in the solution and may act as cyanide
pump.21 Thus, starting from a-aminonitriles 1 and 2,
arylation reactions can be conducted by simply adding
dropwise the organozinc compound to the heated solu-
tion of the a-aminonitrile (method B). This procedure,
which was established considering the important degra-
dation of electron-poor organozinc reagents in the
course of time, might also be adapted to electron-rich
organozinc compounds since they are at the same time
more stable and reactive. Nevertheless, if one considers
the case of the electron-rich organozinc reagent 5a, a
simpler one-pot reaction can be carried out. Indeed,
addition of cuprous iodide raises significantly the rate
of the reaction (method A). When the a-aminonitrile is
enough reactive, the reaction proceeds very fast (ca.
15 min, entry 4) without using cuprous iodide (method
C). Cuprous salts, which are known to enhance nucleo-
philicity of organozinc compounds22 could not be used
with electron-poor organozinc reagents 5b and 5c.
Indeed, addition of cuprous iodide to these organozinc
compounds gave rise to their fast dimerization into the
corresponding biaryls and the formation of metallic cop-
per indicating that a fast redox reaction occurs. In order
to rationalize procedures, the addition of a strong Lewis
acid like AlCl3 might also be considered starting from a-
aminonitriles. This could provide versatile reaction con-
ditions starting from both methoxylated and cyanated
heterocycles. Several attempts in this goal are now in
progress.
For the synthesis of 2-methoxy-tetrahydropyran (4),
methanol and 3,4-dihydro-2H-pyran were allowed to re-
act in the presence of a catalytic amount of concentrated
hydrochloric acid yielding almost quantitatively the
expected compound.18
These masked iminium or oxonium equivalents were
allowed to react with several aromatic organozinc
reagents, prepared in acetonitrile according to a cobalt-
catalyzed procedure developed in our laboratory.19
In a typical procedure, to the filtered acetonitrile solu-
tion (ca. 20 mL) of the aromatic organozinc compound
(ca. 10 mmol) obtained as previously described,19a was
added tert-butyl 2-methoxypiperidine-1-carboxylate (3)
(1.08 g, 5 mmol). After a few minutes aluminum trichlo-
ride (1.4 g, ꢀ10 mmol) was added carefully at 0 ꢁC and
allowed to warm for 15 min at room temperature. A
10% NaOH solution (100 mL) was poured into the reac-
tion mixture and organic materials were extracted using
dichloromethane (2 · 100 mL). The organic layer was
dried over potassium carbonate and concentrated to
dryness. Chromatographic purification over silica gel
(eluent pentane/diethyl ether mixture) afforded the cou-
pling product20 in good yield.
Results are reported in Table 1.
These results clearly demonstrate that either a-cyanated
or 2-methoxylated piperidines can be arylated using
functionalized aromatic organozinc reagents. Indeed,
yields are generally good, not only with electron donat-
ing substituents connected to the phenyl ring (entries 1
and 4–8) but even with electron withdrawing groups
(entries 2, 3 and 9).
Examination of reactions involving N-Boc protected
piperidine 3 (entries 5 and 6) showed the simultaneous
arylation and deprotection to give the expected free
amines 8a and 8d. Such deprotections of carbamates
have already been observed in the presence of ZnBr2.23
Different methods are employed in order to realize the
coupling reaction, depending on the reactivity and sta-
bility of organozinc compounds. To summarize, 2-meth-
oxylated heterocycles 3 and 4 can be displaced using
organozinc reagents and aluminum trichloride (method
D). Such a Lewis acid is required since in its absence,
Results presented in entries 7–9 indicate that methoxy-
lated tetrahydropyran also react efficiently in the pres-
ence of aluminum trichloride. This leads us to hope

E. Le Gall et al. / Tetrahedron Letters 47 (2006) 455–458
Table 1. Coupling of heterocyclic electrophiles with aromatic organozinc reagents
457
Entry
Electrophile
Organozinc
Coupling methoda
Product
Yield (%)b
1
A
72
ZnBr
MeO
N
N
5a
Ph
CN
Ph
1
OMe
CF3
6a
6b
F3C
N
2
B
62
N
ZnBr
Ph
5b
Ph
CN
1
1
EtO2C
N
3
B
65
N
CO2Et
ZnBr
Ph
5c
Ph
CN
6c
ZnBr
ZnBr
MeO
4
5
C
D
80
75
N
N
CN
5a
5a
Ph
Ph
2
3
OMe
7
MeO
MeO
N
H
N
OMe
OMe
BOC
OMe
OMe
8a
8d
6
7
D
D
68
70
N
H
N
ZnBr
BOC
5d
5a
3
4
ZnBr
MeO
MeO
O
O
OMe
OMe
OMe
9a
8
9
D
D
63
55
O
O
ZnBr
O
O
OMe
OMe
4
4
5d
5e
9d
9e
ZnBr
EtO2C
CO Et
a Method A: CuI (0.6 g, 30% mol/mol) was added to the filtered organozinc solution (ca. 20 mL containing ca. 10 mmol reagent) and after 5 min,
compound 1 (10 mmol) was added. The mixture was then stirred at rt for 3 h; Method B: The filtered organozinc solution (ca. 20 mL containing ca.
10 mmol reagent) was added dropwise (ca 2 h) to a boiling acetonitrile solution of the aminonitrile 1 (10 mmol); Method C: The filtered organozinc
solution (ca. 20 mL containing ca. 10 mmol reagent) and the aminonitrile 2 (5 mmol) were allowed to react at rt for 15 min; Method D: To the
filtered organozinc solution (ca. 20 mL containing ca. 10 mmol reagent) was added 3 or 4 (5 mmol) and after a few minutes AlCl3 (ꢀ10 mmol) at
0 ꢁC. The mixture was then allowed to react at rt for 15 min.
b Isolated yield.
that other oxygen-containing heterocycles can also be
arylated in the same manner.
In conclusion, these results show that aromatic organo-
zinc reagents allow the efficient nucleophilic displace-

458
E. Le Gall et al. / Tetrahedron Letters 47 (2006) 455–458
10. Chandrasekhar, S.; Raji Reddy, Ch.; Ahmed, M. Synlett
2000, 1655–1657.
11. (a) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117–
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located to the a-position of nitrogen- or oxygen-contain-
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a-aryl piperidines or 2-aryl tetrahydropyrans.
12. Bernardi, L.; Bonini, B. F.; Capito, E.; Dessole, G.; Fochi,
M.; Comes-Franchini, M.; Ricci, A. Synlett 2003, 1778–
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(200 or 300 MHz), 13C NMR (50 or 75 MHz), HRMS and
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´ ´
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